Hydrochloric Acid → Methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate

HRID 921746ノート

反応式

HRID 921746 の反応式
Br[C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6](Br)[C:7]=1[F:8].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:76][N:77]1[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]1.C(=[NH:96])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[NH2:96][C:2]1[CH:3]=[C:4]([N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:11](=[O:14])[O:12][CH3:13])[CH:5]=[C:6]([N:80]2[CH2:81][CH2:82][N:77]([CH3:76])[CH2:78][CH2:79]2)[C:7]=1[F:8]

参加物

9

反応物 6

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 531671-MethylpiperazineHCID 136809Benzophenone imineHCID 634876Binap, (A+-)-HCID 86708628Methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate

生成物 1

HCID 86708629Methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate収率 69.1%

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 312751,4-Dioxane溶媒2 回

反応条件

温度
90 °C

実験手順

A round bottom flask was loaded with methyl (3,5-dibromo-4-fluorophenyl)(4-methoxybenzyl)carbamate (350 mg, 0.744 mmol), (S)-BINAP (69.5 mg, 0.112 mmol), Cesium carbonate (969 mg, 2.97 mmol) and Pd2dba3 (34.1 mg, 0.037 mmol). The flask was evacuated and filled with nitrogen 3 times. Dioxane (10 mL) and 1-methylpiperazine (0.091 mL, 0.818 mmol) were added and the vial evacuated and filled with nitrogen 3 times. The reaction mixture was heated to 90° C. for 20 hours. Benzophenone imine (0.187 mL, 1.116 mmol) was added, the temperature increased to 110° C. and stirring under nitrogen continued for 24 hours. The reaction mixture was cooled to room temperature (immersed into a room temperature water bath). Dioxane (10 ml) and aq. HCl (1.0 molar, 10 ml, 10 mmol) were added and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was partitioned between EtOAc and aq. NaHCO3 solution. The organic layer was washed with NaHCO3 solution and brine, then dried over MgSO4, filtered and concentrated in vacuum. The crude was purified by column chromatography on silica (80 g cartridge, gradient from 100% EtOAc to 20% MeOH in EtOAc) gave methyl (3-amino-4-fluoro-5-(4-methylpiperazin-1-yl)phenyl)(4-methoxybenzyl)carbamate (207 mg)

後処理

  1. customThe flask was evacuated
  2. additionfilled with nitrogen 3 times
  3. customthe vial evacuated
  4. additionfilled with nitrogen 3 times
  5. temperaturethe temperature increased to 110° C.
  6. temperatureThe reaction mixture was cooled to room temperature (
  7. customimmersed into a room temperature
  8. stirringthe reaction mixture stirred at room temperature for 2 hours
  9. customThe reaction mixture was partitioned between EtOAc and aq. NaHCO3 solution
  10. washThe organic layer was washed with NaHCO3 solution and brine
  11. dry with materialdried over MgSO4
  12. filtrationfiltered
  13. concentrationconcentrated in vacuum
  14. customThe crude was purified by column chromatography on silica (80 g cartridge, gradient from 100% EtOAc to 20% MeOH in EtOAc)

出典と根拠

ORDレコード
ord-5dd90a9e229a411090f79d9763edb77d
出典データセット
uspto-grants-2016_03
特許番号
US09273057B2

反応ノート

読み込み中…